DESCRIPTION: (Principal Investigator's Abstract) The medicinal chemist relies on the tools of organic synthesis to prepare new therapeutic agents, or to prepare molecules to study the mechanism of action of existing therapeutic agents. Given the importance of chirality in the biological activity of drugs, medicinal chemists need methods for the preparation of enantiomerically and diastereomerically pure molecules. This grant supports a research program the aims of which are to discover new stereoselective and chemoselective reactions and reagents in organic synthesis. The tools of mechanistic organic chemistry are used to study the mechanism of action of selective reagents and catalysts. The results of these studies are then used to devise new reagents and catalysts that offer advantages over the original. In this proposal, a continuation of work on the development of enantioselective reducing agents for ketones and aldehydes using chiral ruthenium complexes is described. The use of these complexes in the kinetic resolution of chiral alpha- and beta-alkoxy aldehydes and ketones will be studied. A second chiral reducing agent is described that is based on work undertaken in the last funding period wherein hydroxyl-directed catalysts which bear separate binding and catalytic sites were designed and their mechanisms studied. This reducing agent is derived from the Corey-Bakshi-Shibata (CBS) catalyst which has been rendered alkoxy-directed by the incorporation of a binding site. As in the ruthenium derived system, the kinetic resolution of chiral alpha- and beta-alkoxy aldehydes and ketones will be studied with this catalyst. Also, the synthesis of skipped 1,3,5-triols will be undertaken, the application of this chemistry being to the synthesis of the antifungal agent mycoticin. A second project relates to the use of vinyl oxocarbenuim ions in the ionic Diels-Alder reaction. This ongoing project focuses on studying the stereoselectivity of this reaction, especially in systems which can display remote asymmetric induction. Finally, the synthesis of substituted heterocycles using variants of the halogen dance and the newly ,discovered tin dance reaction is described.